Celastrol Blocks Neuronal Cell Death and Extends Life in Transgenic Mouse Model of Amyotrophic Lateral Sclerosis
Celastrol Blocks Neuronal Cell Death and Extends Life in Transgenic Mouse Model of Amyotrophic Lateral Sclerosis
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DOI：
10.1159/000090364
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发表时间：
2005-01-01
影响因子：
3
通讯作者：
Beal, M. Flint
中科院分区：
文献类型：
--
作者：
Kiaei, Mahmoud;Kipiani, Khatuna;Beal, M. Flint
有大量证据表明，炎症和氧化损伤都有助于肌萎缩侧索硬化症（ALS）的G93 A SOD 1转基因小鼠模型中运动神经元变性的发病机制。南蛇藤酚是一种产自中国南方的天然产物，具有很强的抗炎和抗氧化作用。它还有效地增加热休克蛋白（包括HSP 70）的表达。我们从30日龄开始将其在饮食中给予G93 A SOD 1小鼠。雷公藤红素治疗显著改善了体重减轻、运动表现并延迟了ALS的发作。雷公藤红素处理的G93 A小鼠的存活率在2 mg/kg/天和8 mg/kg/天剂量下分别增加9.4%和13%。腰脊髓神经元的细胞计数证实了保护作用，即雷公藤红素处理的动物的腰脊髓中神经元数量增加30%。与未处理的G93 A小鼠相比，雷公藤红素处理降低雷公藤红素处理的G93 A小鼠的腰脊髓切片中的TNF-α、iNOS、CD 40和GFAP免疫反应性。TNF-α免疫反应性与SMI-32（神经元标记物）和GFAP（星形胶质细胞标记物）共定位。雷公藤红素处理的G93 A小鼠腰髓神经元中HSP 70免疫反应性增加。雷公藤红素已被广泛用于治疗人类炎症性疾病，并且耐受性良好;因此，它可能是治疗人类ALS的有希望的治疗候选物。版权所有（C）2005 S. Karger AG，巴塞尔
There is substantial evidence that both inflammation and oxidative damage contribute to the pathogenesis of motor neuron degeneration in the G93A SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Celastrol is a natural product from Southern China, which exerts potent anti-inflammatory and antioxidative effects. It also acts potently to increase expression of heat shock proteins including HSP70. We administered it in the diet to G93A SOD1 mice starting at 30 days of age. Celastrol treatment significantly improved weight loss, motor performance and delayed the onset of ALS. Survival of celastrol-treated G93A mice increased by 9.4% and 13% for 2 mg/kg/day and 8 mg/kg/day doses, respectively. Cell counts of lumbar spinal cord neurons confirmed a protective effect, i.e. 30% increase in neuronal number in the lumbar spinal cords of celastrol-treated animals. Celastrol treatment reduced TNF-alpha, iNOS, CD40, and GFAP immunoreactivity in the lumbar spinal cord sections of celastrol-treated G93A mice compared to untreated G93A mice. TNF-alpha immunoreactivity co-localized with SMI-32 (neuronal marker) and GFAP (astrocyte marker). HSP70 immunoreactivity was increased in lumbar spinal cord neurons of celastrol-treated G93A mice. Celastrol has been widely used in treating inflammatory diseases in man, and is well tolerated; therefore, it may be a promising therapeutic candidate for the treatment of human ALS. Copyright (C) 2005 S. Karger AG, Basel